1074 Journal of Medicinal Chemistry, 1975, Vol. 18, No. 11
(2) (3) (4) (5)
(6) (7)
(8) (9) (10)
For the previous paper in this series, see M. J. Robins, G . Ramani, and M. MacCoss, Can. J . Chem., 53,1302 (1975). (a) M. J. Robins and B. L. Currie, Chem. Commun., 1547 (1968). (b) B. L. Currie, R. K. Robins, and M. J. Robins, J . Heterocycl. Chem., 7,323 (1970). M. J. Robins, B. L. Currie, R. K. Robins, and A. Bloch, Proc. Am. Assoc. Cancer Res., 10,73 (1969). B. L. Currie, M. J. Robins, and R. K. Robins, J . Heterocycl. Chem., 8, 221 (1971); M. J. Robins, B. L. Currie, R. K. Robins, and A. D. Broom, Can. J. Chem., 49,3067 (1971). A. Bloch, G. Dutschman, B. L. Currie, R. K. Robins, and M. J. Robins, J . Med. Chem., 16,294 (1973). (a) S. Nesnow, T. Miyazaki, T. Khwaja, R. B. Meyer, Jr., and C. Heidelberger, J . Med. Chem., 16, 524 (1973); (b) R. L. Shone, Tetrahedron Lett., 3079 (1973). R. W. Brockman, S. C. Shaddix, M. Williams, and D. A. Nelson, Ann. N.Y. Acad. Sci., in press (presented by Dr. Brockman a t the Conference on the Chemistry, Biology, and Clinical Uses of Nucleoside Analogs, New York, N.Y., Sept 6 6 , 1974.) R. P. McPartland, M. C . Wang, A. Bloch, and H. Weinfeld, Cancer Res., 34,3107 (1974). M. C. Wang and A. Bloch, Biochem. Pharmacol., 21, 1063 (1972). W. M. Shannon, G. Arnett, and F. M. Schabel, Jr., Antimicrob. Agents Chemother., 2, 159 (1972); W. M. Shannon, R. W. Brockman, L. Westbrook, S. Shaddix, and F. M. Schabe!,
Barber. Rapoport Jr., J . Natl. Cancer Inst., 52,199 (1974);G. Khare, R. W. S i i well, J. H. Hoffman, R. L. Tolman, and R. K. Robins, Proc. SOC. Exp. Biol. Med., 40,880 (1972). (11) C. H. Schwalbe, H. G. Gassen, and W. Saenger, Nature (London), New Biol., 238,171 (1972). (12) H. G. Gassen, H. Schetters, and H. Matthaei, Hiochim. Hiophys. Acta, 272,560 (1972). 113) See for example (a) M. J. Robins, S. It. Naik, and A. S. K. Lee, J . Org. Chem., 39, 1891 (1974); (b) J. T. Kusmierek, J . Giziewicz, and D. Shugar, Biochemistry, 12, 194 (1973),and references cited therein. (14) See, for example, M. Honjo, Y. Kanai, Y. Furukawa, Y.Mizuno, and Y. Sanno, Riochim. Bioph,ys. Acta, 87, 696 (1964); Y. Furukawa, K. Kobayashi, Y. Kanai, and M. Honjo, Cheni. Pharm. Buil, 13, 1273 (1965); L. Hudson, M. Gray, and B. G. Lane, Hiochemistry, 4,2009 (1965). (15) M. J. Robins, A. S. K. Lee, and F. A. Norris, Carhohg,dr. Res., 41,304 (1975). 116) H. Zollinger, “Azo and Diazo Chemistry”, Interscience, New York, N.Y., 1961, pp 69-70, 102-104. (17) C. A. Dekker, J. Am. Chem. Soc., 87,4027 (1965). (18) H. J. den Hertog and D. J. Buurman. Recl. Trar:. Chim. PaysHas, 75, 257 (1956). (19) D. M. G. Martin, C. B. Keese, and G. F. Stephenson, Hiochemistry, 7, 1406 (19681. (20) S. ,J. Shaw, D. M. Desiderio, K. Tsuboyama, and ,I. A. McCloskey, J . Am. Chem. Soc., 92,2510 (1970).
Synthesis of Thebaine and Oripavine from Codeine and Morphine Randy B. Barber and Henry Rapoport* Department of Chemistry, University of California, Berkeley, California 94720. Received June 16, 1975
A practical synthesis of thebaine and oripavine has been developed from codeine and morphine, respectively. Attempts to use a codeinone intermediate gave poor yields; however, methylation of the potassium salt of codeine to give codeine methyl ether followed by oxidation with y-MnOz gave thebaine in 67% yield from codeine. Similarly, the potassium salt of the di-0-anion of morphine was selectively alkylated t o give morphine 6-methyl ether (heterocodeine) in better than 90% yield. Heterocodeine was then acetylated and oxidized to oripavine 3-acetate which was hydrolyzed to give oripavine in 73% yield from morphine.
Thebaine is the least abundant among the hydrophenanthrene alkaloids in P a p a v e r somniferum, and it has no medicinal use in itself. Yet it is singularly important as the key intermediate in the synthesis of many useful opiate derivatives. This is uniquely the case for the naloxone family of opiate antagonists’ and for the highly potent oripavine derivatives initiated from the Diels-Alder adducts of thebaine.* The significant increase of opiate abuse in the United States, starting in the late 1960’s, focused attention on the potential role of antagonists and raised the real danger of a thebaine ~ h o r t a g e .This ~ danger was aggravated by the temporary cessation of opium cultivation in Turkey which stimulated the search for new sources of thebaine such as P. b r a ~ t e a t u r nWith . ~ the ebb and flow of drug diplomacyj now resulting in the resumption of Turkish opium cultivation, P . somniferum appears to be restored as the most abundant and efficient source of the medicinal opiates. We have sought to develop a practical and economic method for the synthesis of thebaine from the more available alkaloids of P . somniferum, morphine and codeine. Corollary to this is our objective of devising a ready source of oripavine, which is naturally occurring in very minor amounts in P . b r a c t e a t ~ m .Readily ~.~ available oripavine is of interest since its use may obviate the final and difficult 0-3-methyl ether cleavage in the synthesis of the DielsAlder derived narcotics.2
The literature teaches three methods for the synthesis of thebaine ( t a ) .The first7 converts dihydrocodeinone to thebaine in four steps in 27% yield. Considering the preparation of dihydrocodeinone from codeine: this leads to a 20% overall yield from codeine. Although this conversion could undoubtedly be improved, the improvement is limited and the process inconvenient since six steps are involved. The second processg involves direct methyl enol ether formation from codeinone and claims a 27% yield of thebaine; further comments on this process are given below. The third processlo is a total synthesis in which the key step is the oxidative coupling of a reticuline derivative to a salutaridine derivative. While the yields in this coupling step have been improved dramatically (by a factor of 1000), the overall yield of dl- thebaine remains in the 1-2% range, based on isovanillin.
Discussion In considering the conversion of codeine (lb) to thebaine (2a), the two changes which must be effected, both in ring C, are oxidation (removal of two hydrogens) and methylation (formation of a methyl ether at 0-6). Our first attempts followed the common pathway, namely, first oxidation to codeinonel’ and then formation of the methyl enol ether directly or via the dimethyl ketal and methanol elimin a t i ~ nThis . ~ is the same path as followed recentlyYand our
Thebaine and Oripavine
efforts were focused on finding better methods for effecting the second step. Direct acid-catalyzed enol.ether formation gave the best yield with 1-propanol, 37% of codeinone n-propyl enol ether. Extensive study and variation of the conditions (time, temperature, acidity, concentration) led to no improvement,12 and our maximum yields of thebaine (2a) were in the 15-20% range.13 We then explored a variety of different enol ether and ketal forming reagents. (1) Transketalization with 2,2-dimethoxypropane, trimethyl orthoformate, or dimethylformamide dimethyl acetal and (2) methyl dienol ether formation with acetimino methyl ether hydrochloride, 0-methyl-N,N'- dicyclohexylisourea, and 0-methyl-N,N'- dicyclohexylisourea hydrochloride were investigated. None of these methods yielded the desired products and in most cases gave either no reaction or underwent 1,4 addition to the a$-unsaturated ketone.?
Rj la b
H CHJ CH3 H COCH, COC6H, H
Journal of Medicinal Chemistry, 1975, Vol. 18, No. 11 1075
taining carbonyl groups but is seldom effective for introducing carbon-carbon double bonds, although such reactions are known.17 Most of these reactions were performed using the active manganese dioxide as prepared by Attenburrow,I8 and similar results are obtained with MnOz on charcoal. l9 This is the first example of the oxidation of an allylic ether to a dienol ether with manganese dioxide. In seeking other applications for this process, we attempted the oxidation of isocodeine methyl ether (i-CME) and geranyl methyl ether. Neither was oxidized to a dienol methyl ether; both were recovered unchanged. Thus, this reaction does not appear to be general, and the reason for its successful use may be steric. In the case of CME, the two hydrogens being removed are 1,4-cis-diaxial; however in i-CME, the hydrogens being removed are trans. In this regard, it is interesting that i-CME also is not oxidized by DDQ.
H
I
H
codeine methyl ether
H
I
OCH,
isocodeine methyl ether
Isocodeine methyl ether was obtained from isocodeine in c a manner analogous to the' formation of codeine methyl d ether from codeine. Isocodeine was prepared in 71% yield e by inversion of codeine via reaction with dimethylformamf ide dineopentyl acetal and acetic acid to yield isocodeine g 6-acetate which was then hydrolyzed. This method for the inversion of saturated secondary alcoholsz0 is thus applicaFailure of the oxidation-methylation sequence to ble to an allylic alcohol. Preparation of isocodeine by this achieve a practical conversion of codeine to thebaine led us process is comparable in yield (65-70%) and easier to perto investigate the reverse procedure, that is, methylation form than the procedure via codeine 6 - t o ~ y l a t e . ~ ~ first followed by oxidation. The requisite codeine methyl The synthesis of oripavine from morphine was patterned ether (IC, CME) has been prepared by a method which inafter the synthesis of thebaine from codeine. We first volves 0- and N-methylation followed by dequaternizathought that the phenolic group of morphine would have to tion.'* A significantly improved method was developed in be protected in order to get selective methylation of the which the potassium salt of codeine was methylated with 6-OH; therefore, morphine 3-benzoate (If) was prepared methyl iodide to give CME in 83% yield. The yield was less analogously to the reported method for morphine 3-acewith the sodium salt and zero with the lithium salt. tate.22 However, attempts to methylate morphine 3-benzoOxidation of CME was first attempted by brominationate gave mostly morphine 6-benzoate (lg).The alternatives dehydrobromination. Under a large variety of conditions, were either to find another blocking group or to attempt seneither bromine addition nor allylic bromination occurred; lective methylation of morphine directly. The latter alterthe exclusive product was 1-bromocodeine methyl ether. native was selected, and the dipotassium salt of the di-0Direct catalytic dehydrogenation was then attempted by anion of morphine, when treated with methyl iodide, gave heating with PdIC, but CME was recovered unchanged. morphine 6-methyl ether (Id, heterocodeine) in 92% yield. Successful conversions to thebaine were obtained when CME was oxidized with 2,3-dichloro-5,6-dicyano-1,4- The phenolic group at C-3 of heterocodeine was then blocked as the acetate. Oxidation with y-MnOZ and hydrolbenzoquinone (DDQ) or o-chloranil. DDQ was the more efysis gave oripavine in an overall yield of 73% from morfective oxidizing agent, and the reaction with it and CME phine. proceeded more rapidly than with o -chloranil. The reaction with DDQ requires a t least 2 equiv of DDQ, the first equivExperimental Section23 alent forming a benzene-insoluble complex with CME. Codeine Methyl Ether (IC). An excess of potassium hydride Since DDQ is a relatively expensive reagent, especially (300 mol %, 35% dispersion in oil) was washed with hexane (3 X 50 when used in 300 mol % stoichiometry, and since the reacml, distilled from CaH2) and then suspended in T H F (50 ml, distion yields a crude mixture (about 1:l) of CME and thetilled from LiAlHd). With stirring under a nitrogen atmosphere, a baine, we examined some other oxidants such as CrOT solution of codeine (1.00 g, 2.33 mmol) in 50 ml of T H F was added Pyz,15 selenium dioxide, and manganese dioxide. Both to the KH suspension over a period of 2 hr and stirred for an additional hour. Methyl iodide (0.43 ml, 6.66 mmol) was added to the CrOYPyz and SeOz consumed codeine methyl ether but no mixture rapidly and the reaction was quenched after 90 sec with 20 thebaine was detected. ml of 1 N NaOCzHs in ethanol. Water (50 ml) was added and the Best results have been obtained from the reaction of cosolution evaporated to remove organic solvents. The resulting deine methyl ether with y-MnOzI6 to give thebaine in 80% aqueous mixture was extracted with chloroform (4 X 50 ml), and yield (67% overall from codeine). Manganese dioxide has the chloroform extracts were washed with a small portion of water, been used to oxidize benzylic and allylic alcohols to ketones dried over MgS04, and evaporated to give a crude solid which was crystallized from ethanol to give 0.87 g (83%),mp 138-139' (lit.I4 and aldehydes and certain tertiary amines to products con-
1076 Journal of Medicinal Chemistry, 1975, Vol. 18,No. 11 mp 140-141°), identical with an authentic sample of codeine methyl ether by TLC, GC, mass spectrum [m/e 313 (M+)],and NMR. Thebaine (2a). A. B y Oxidation with DDQ. To a stirred solution of codeine methyl ether (156 mg, 0.5 mmol) in 5 ml of benzene under a nitrogen atmosphere was added 2,3-dichloro-5,6-dicyano1,4-benzoquinone (DDQ) (119 mg, 0.525 mmol) and the dark green precipitate (272 mg) which formed was collected by filtration. The filtrate yielded 7 mg of CME. When 50 mg of the precipitate was partitioned between chloroform and aqueous NaHC03, 28 mg of CME was recovered from the chloroform layer. The green precipitate (50 mg) was suspended in 5 ml of benzene and another portion of DDQ (22 mg, 0.097 mmol) was added and the mixture was boiled overnight. The precipitate (64 mg), now red brown, was collected by filtration and was partitioned between chloroform and aqueous NaHC03 to give in the CHCls phase 26 mg of an oil which by TLC and GC contained CME and thebaine in a 1:l ratio. B. By Oxidation with Chloranil. Codeine methyl ether (159 mg, 0.508 mmol) was refluxed with o-chloranil (131 mg, 0.535 mmol) in 5 ml of benzene under a nitrogen atmosphere for 6 hr. After the usual work-up GC analysis showed 70% CME remaining and a small portion of thebaine. C. By Oxidation with 7-MnO2. A solution of codeine methyl ether (313 mg, 1.00 mmol) in T H F (10 ml, distilled from LiAlH4) was shaken vigorously with y-MnOz (440 mg, 5.0 mmol) under a nitrogen atmosphere a t room temperature. Further portions of y MnO2 (440 mg, 5.0 mmol) were added a t intervals of 1, 3, 5, and 10 hr. After 24 hr the black mixture was filtered through a fine sintered glass funnel, the residue was washed with T H F (4 X 50 ml), and the washings were combined with the original filtrate and evaporated to give 207 mg of crude thebaine. The MnO2 was then washed with methanol (4 X 30 ml) which yielded an additional 119 mg of crude thebaine. The two fractions were combined and crystallized from ethanol to give thebaine (251 mg, 80%) identical with an authentic sample by mp (191-192'), TLC, GC, mass spectrum [mle 311 (M+)],and NMR. Morphine 6-Methyl Ether (Heterocodeine, Id). Potassium hydride (57.0 g, 331 mmol, 27% dispersion in oil) was washed with dry hexane, suspended in T H F (1000 ml, distilled from LiAlH4), and cooled in an ice bath under a nitrogen atmosphere. A solution of morphine monohydrate (11.4 g, 37.5 mmol) in 1 1. of T H F was added slowly, and the resulting white suspension was stirred for 6 hr and allowed to warm to room temperature. Methyl iodide (2.7 ml, 43.4 mmol) was added and an aliquot of the reaction was analyzed after 25 min by GC; no morphine remained and only heterocodeine was present. The reaction was quenched by slowly adding water and cooling in an ice bath. The solution was neutralized to pH 7, the T H F was evaporated, the pH of the solution was readjusted to 12.5, and it was extracted with chloroform to remove any phenolic methyl ether. The pH was then adjusted to 8.6 and the solution extracted with chloroform-2-propanol (3:l). This extract was evaporated to give a brown oil from which heterocodeine (9.44 g) was crystallized from ethyl acetate. The mother liquor was chromatographed on thin layer (CHC13-CH30H-NH40H, 3:1:1%) to give additional heterocodeine (0.82 g): total yield, 91.6%; mp 242243O (lit.24mp 242'); NMR 6 2.5 (s, 3 H), 3.5 (s, 3 H), 4.9 (d, 1 H , J = 3 Hz), 5.5 (m, 2 H), 6.5 (9, 2 H, J = 4 Hz); mass spectrum mle 299 (M+). Morphine 3-Acetate 6-Methyl Ether (Heterocodeine 3-Acetate, le). Acetic anhydride (0.35 ml, 3.70 mmol) was added to a solution of heterocodeine (0.97 g, 3.25 mmol) in pyridine (7.5 ml, distilled from BaO) a t room temperature and under a nitrogen atmosphere. After 2.5 hr the reaction was complete (TLC and GC) and it was quenched with ice and water (125 ml). The resulting aqueous solution was extracted with chloroform (4 X 100 ml), and the chloroform extracts were washed with water, dried over Na2S04, and evaporated to give 1.08 g (97%) of heterocodeine 3-acetate (le): mp 133.5-134.0'' on crystallization from ethanol; NMR 6 3.5 (6-OCHs), 2.5 (NCH3), 2.18 (OCOCH3); mass spectrum mle 341 (M+).Anal. (C~oH23N04)C, H , N. Oripavine 3-Acetate (2b). Portions of y-MnO2 (5 X 440 mg, 5 x 5.0 mmol) were added to a solution of heterocodeine 3-acetate (le, 341 mg, 1.0 mmol) in T H F (50 ml, distilled from sodium benzoketyl) a t intervals of 1, 2, 3, and 4 hr a t room temperature with shaking. After a total of 24 hr of shaking the reaction mixture was filtered and the precipitate was washed with fresh T H F C4 X 50 ml) which was combined with the filtrate and evaporated to give a tan foam of 264 mg, homogeneous by TLC. The precipitate was then washed with methanol 4 X 50 ml) to give an additional 82 mg which contained a trace of le. The two residues were combined and crystallized from ethanol to give oripavine 3-acetate (2b) in
Barber, Kapoport 88% yield: mp 173O; NMR showed the expected quintet in the 56-ppm region for the 5, 7, and 8 protons; mass spectrum m l e 339 (M+);homogeneous by TLC. Anal. (C20H21N04) C, H, N. Oripavine (2c). Oripavine 3-acetate (Zb, 224 mg, 0.67 mmol) was dissolved in methanol-water (4:1, 25 ml) and 2 N NaOH (2 ml) was added. Reaction was complete in less than 2 min (TLC). 14 ml of water was added, the p H was lowered to 8, and the methanol was evaporated. The resulting aqueous solution was adjusted to pH 8.9 and extracted with chloroform-2-propanol (31. 5 x 50 ml). The extracts were combined, washed with aqueous NaHCO: (saturated, 2 X 75 ml), dried over Na2S04, and evaporated to give 184 mg (93%) of oripavine (212): homogeneous by TLC; mass spectrum m l e 297 (M+);mp 199-200' (lit.4 mp 200-201°); NMR, same as thebaine minus 3-OCHz. Isocodeine. A mixture of dimethylformamide dineopentyl acetal (17.3 ml, 60.0 mmol) and glacial acetic acid (3.6 ml, 60.0 mmol) in toluene (60 ml, dried over Na) was added in two portions 3 hr apart t u a solution of codeine (3.00 g, 10.0 mmol) in toluene ( 2 5 0 ml) heated to 80' under a nitrogen atmosphere with stirring. The reaction solution was then stirred and heated at 80" for an additional 21 hr, after which 100 ml of o-xylene was added and the mixture evaporated at SOo. o-Xylene was added and evaporated twice more to give crude isocodeine &acetate. The crude isoci)deine acetate was hydrolyzed with aqueous methanolic NaOH ti) give a crude solid which was crystallized from ethanol yielding 2.1 2 g (71%) of isocodeine: mp 173.5-174.5' (lit,21mp 17:3--174'); homogeneous by TLC and GC; mass spectrum m / e M+ 297; and NMR consistent with the literature." Isocodeine Methyl Ether. Isocodeine (297 mg, 1.00 mmol) was treated in a similar fashion as in the preparation of codeine methyl ether to give 283 mg of an oil which contained isocodeine and isocodeine methyl ether. This mixture was separated by preparative thin-layer chromatography to give 167 mg of isocodeine methyl ether (mp 94.5-95' from ethanol) and 32 mg of isocodeine, each homogeneous by TLC and GC. The isocodeine methyl ether had a mass spectrum m l e 313 (M+); its NMR was the 5ame as that of isocodeine except for the presence of 6-0-methyl absorption a t 6 3.6 (s, 3 Hi. Anal. (CIgH23NO3) C, H, N. Geraniol Methyl Ether. Geraniol (1.00 g, 6.5 mmol) was treated in a similar fashion with KH and methyl iodide as in the preparation of codeine methyl ether to give an oil: 0.56 g (51%); bp 8588' ( 8 mm) [lit.2s bp 100-105° (10 mm)]; NMR same as geraniol plus an 0-methyl absorption a t 8 3.3 (s, 3 Hj. Bromination of Codeine Methyl Ether. 1-Bromocodeine Methyl Ether. To a stirred solution of 500 mg of codeine methyl ether in 60 ml of methylene chloride in a nitrogen atmosphere and cooled in a Dry Ice-acetone bath was added, over 0.5 hr, a cooled solution of 368 mg of bromine in 30 ml of methylene chloride. Potassium hydrosulfite (1.0 g) and saturated potassium carbonate solution (50 ml) were added, the mixture was removed from the cooling bath, and the organic phase was separated. Evaporation of the methylene chloride after washing and drying gave a residue 1631 mg) which was chromatographed on silica gel, eluting with methanol-chloroform (1:3j. Recovered codeine methyl ether and l-bromocodeine methyl ether were obtained; crystallization from methanol gave the 1-bromo compound of mp 159'. Anal. (CIgHZ2BrNOd C. H, N. Bromination in carbon tetrachloride gave the same result as did the use of tetramethylammonium tribromide and free-radical bromination with N-bromosuccinimide.2fi
Acknowledgment. This research was supported in part by the National Institute on Drug Abuse. References and Notes (1) J. F. Cavalla, Annu. Rep. M e d . Chem., 4, 37 (1968); F. M. Robinson, ibid., 7 (1972). (2) K. W. Bentley and D. G. Hardy, J . Am. C h e m . Soc., 89, 31181 (1967); J. Lewis, K. W. Bentley, and A. Cowan, Annu. K e u PhQrmQCol.,11,241 (1970). (3) "A National Research Program to Combat the Heroin Addiction Crisis", House Report No. 92-678, Select Committee on Crime, Claude Pepper, chairman, 92nd Congress of the U.S.A., 1st session, 1971; Science, 173, 503 (1971). (4) V. V. Kiselev and R. A. Konovalova, J . Gen. Chem. L'SSK. 18, 142, 855 (1948); D. Neubauer, Arch. Pharm. ( W e i n h e i m , Ger.), 298, 47 (1965); N. Sharghi and L . Lalezari. IYcItuw (London),213,1244 (1967). (5) For a perceptive critique of international opium politics and the futility of some recent political control measures, see M.
Aromatic Guanidine Compounds Gordon, Annu. Rep. Med. Chem., 9,39 (1973). (6) The relative amounts of thebaine, oripavine, codeine, and morphine, and their biosynthesis, in P. bracteaturn will be the subject of subsequent publications from this laboratory. (7) H. Rapoport, C. H. Lovell, H. R. Reist, and M. E. Warren, J. Am. Chem. SOC.,89,1942 (1967); U. Eppenberger, M. E. Warren, and H. Rapoport, Helv. Chim. Acta, 51,381 (1968). (8) H. Rapoport, R. Naumann, E. R. Bissell, and R. M. Bonner, J . Org. Chem., 15,1103 (1950). (9) I. Seki, Chem. Pharm. Bull., 18,671 (1970). (10) M. A. Schwartz and I. S. Mami, J . Am. Chem. SOC.,97, 1239 (1975). (11) H. Rapoport and H. N. Reist, J . Am. Chem. SOC.,77, 490 (1955). (12) Experiments by Dr. E. J. Racah, this laboratory. (13) A 27% yield of thebaine from codeinone is reported in ref 9. (14) C. Mannich, Arch. Pharm. (Weinheim, Ger.), 254,349 ([9[6(/ (15) R. Ratcliffe and R. Rodehorst, J . Org. Chem., 35,4000 (1970). (16) L. I. Vereshchagin, S. R. Gainulina, S. A. Podskrebysheva, L. A. Gaivoronskii, L. L. Okhapkina, V. G. Vorobeva, and V. P. Latyshev, Zh. Org. Khim., 8, 1129 (1972). (17) D. Walker and J. D. Hiebert, Chem. Rev., 67, 153 (1967); P. K. Martin, H. R. Matthews, H. Rapoport, and G. Thyagarajan, J . Org. Chem., 33,3758 (1968).
Journal of Medicinal Chemistry, 1975, Vol. 18, No. 11
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(18) J. Attenburrow, A. F. B. Cameron, J. H. Chapman, R. M. Evans, B. A. Hems, A. B. A. Jansen, and T. Walker, J . Chem. Soc., 1094 (1952). (19) L. A. Carpino, J. Org. Chem., 35,3971 (1970). (20) H. Vorbruggen, Justus Liebigs Ann. Chem., 821 (1974). (21) G. N. Kirby and S. R. Massey, or. Chem. SOC. C, 3047 (1971). (22) J. Fishman, B. Norton, M. L. Cotter, and E. F. Haha;, J . Med. Chem., 17,778 (1974). (23) Solvent evaporations were carried out in vacuo using a Berkeley rotary evaporator. All melting points are uncorrected. Gas chromatography was performed on a glass column packed with OV-17 on Aeropac 30; thin-layer chromatograms were in silica gel and were developed with CHC13-CH30H (85:15) unless otherwise specified; nuclear magnetic resonance spectra were taken in CDC13; and mass spectra were obtained on CEC 103 and llOB instruments. Elemental analyses were performed by the Analytical Laboratory, Department of Chemistry, University of California, Berkeley. (24) L. F. Small and R. E. Lutz, “Chemistry of the Opium Alkaloids”, Suppl. 103, Public Health Report, US. Government Printing Office, Washington, D.C., 1932. (25) R. F. Bacon, Chem. ZentralbL, 2,945 (1908). (26) K. Dittmer, R. P. Martin, W. Herz, and S. J. Cristol, J. Am. Chem. SOC., 71,1201 (1949).
Cardiovascular Activity of Aromatic Guanidine Compounds John L. Hughes,* R. C. Liu, T. Enkoji, Organic Chemistry Department
Carroll M. Smith, James W. Bastian, and Pedro D. Luna Pharmacology Department, Armour Pharmaceutical Company, Kankakee, Illinois 60901. Received December 5,1974 A series of aromatic guanidines and several 1-phenylbiguanideswas prepared and tested for cardiovascular (CV) effects in anesthetized dogs measuring heart rate, blood pressure, carotid artery blood flow, and myocardial force changes. The predominant CV effect a t minimally effective dose was vasoconstriction unassociated with cardiac stimulation. The structure-activity relationships of the compounds were discussed comparing their structural similarities to the 6-phenylethylamines. The most potent members of the series were phenylguanidines substituted in the 3 and 4 positions on the aromatic nucleus with hydroxy or chloro groups. Preliminary mechanism studies indicated that the 3,4-dihydroxyphenylguanidinesact at least partially by a direct a-adrenergic mechanism.
During a general screening program of organic compounds several phenylguanidine compounds were found to exhibit biological activity similar to the familiar adrenergic action of the /3-phenylethylamine series. Examination of the two significant tautomeric structures and the protonated species of phenylguanidine I, which would be expected
+H+
r
-
-H
I
I1
to exist a t physiologic pH, reveals obvious structural similarity to the @-phenylethylamineseries 11. Both structures I and I1 have aromatic groups and basic amino groups separated by similar distances. The bond distance between the central carbon and each nitrogen of the guanidine nucleus has been reported to be 1.32 A1 in contrast to 1.46 A for an aliphatic carbon to carbon bond. The guanidine compounds would, however, be planar and thus more rigid than the aliphatic portion of the P-phenylethylamine series. Using these considerations as a rationale, a large series of aromatic guanidine and several l-phenylbiguanide compounds were prepared. The pharmacological actions of these compounds were investigated to determine if they possessed potentially useful cardiovascular effects. Chemistry. The guanidine and biguanide moieties of the compounds described in Tables I and I1 were prepared using five different methods. The method selected for each compound was dependent upo;? the location and number of substituents on the guanidine or biguanide nitrogens. For the preparation of the monosubstituted guanidine compounds and the 1,l-disubstituted compounds in Tables I and 11, the well-known reaction of an aromatic amine mineral acid salt and hydrogen cyanamide in a refluxing solution of water or aqueous ethanol was used (method I).* The aromatic amines were obtained commercially or
